CN104447484B - Containing alkoxyphenyl radical and the compound of diene adamantane structure, Preparation Method And The Use - Google Patents
Containing alkoxyphenyl radical and the compound of diene adamantane structure, Preparation Method And The Use Download PDFInfo
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- CN104447484B CN104447484B CN201510017456.3A CN201510017456A CN104447484B CN 104447484 B CN104447484 B CN 104447484B CN 201510017456 A CN201510017456 A CN 201510017456A CN 104447484 B CN104447484 B CN 104447484B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 title claims description 33
- 239000003814 drug Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000001993 dienes Chemical class 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- WKOVRQFUCLHTHB-UHFFFAOYSA-N n-(ethyliminomethylideneamino)-n-methylmethanamine Chemical class CCN=C=NN(C)C WKOVRQFUCLHTHB-UHFFFAOYSA-N 0.000 claims description 2
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000002274 desiccant Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003146 anticoagulant agent Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 5
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 230000000702 anti-platelet effect Effects 0.000 description 3
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 108010070519 PAR-1 Receptor Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000002020 Protease-activated receptors Human genes 0.000 description 2
- 108050009310 Protease-activated receptors Proteins 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 102000003790 Thrombin receptors Human genes 0.000 description 2
- 108090000166 Thrombin receptors Proteins 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000005345 coagulation Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940118340 Indirect thrombin inhibitor Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000032626 PAR-1 Receptor Human genes 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000007466 Purinergic P2 Receptors Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Abstract
The present invention relates to the drug world relevant to thrombotic disease. Specifically, the present invention relates to the class PAR-1 antagonist containing alkoxyphenyl radical and diene adamantane structure, Preparation Method And The Use.
Description
Technical field
The present invention relates to the drug world relevant to thrombus disease. Specifically, the present invention relates to PAR-1 antagonist containing alkoxyphenyl radical and diene adamantane structure of the medicative class of thrombotic disease and preparation method thereof, containing their pharmaceutical composition and purposes on treatment thrombotic disease.
Background technology
Proteinase activated receptors 1 (ProteaseActivatedAcceptor-1, PAR-1) is the novel targets of recently discovered antiplatelet class antithrombotic reagent. Proteinase activated receptors 1 is again thrombin receptor, and thrombin passes through PAR-1 receptor acting in platelet thus activating platelet after being activated by coagulation cascade, causes platelet aggregation thus causing thrombosis and blood coagulation. Rich in platelet component in the thrombosis that PAR-1 causes, it it is the main reason of arterial thrombus. PAR-1 antagonist can block thrombin activation platelet, thus interruption artery thrombosis, it is possible to it is used for treating acute coronary artery disease (AcuteCoronarySyndrome). Several PAR-1 inhibitor has been had to be in clinical research (ChackalamannilS., ThrombinReceptor (ProteaseActivatedReceptor-1) AntagonistsasPotentAntithromboticAgentswithStrongAntipla teletEffects, J.Med.Chem., 2006,49 (18), 5389-5403).
The medicine being traditionally used for preventing and treating thrombotic disease is divided three classes. The first kind is anticoagulation class, it is divided into direct thrombin inhibitor and indirect thrombin inhibitor, such medicine carrys out inhibition thrombosis by acting on the different links of coagulation cascade, has the various thrombotic effects of suppression, such as vitamin K antagon and Xa factor inhibitor etc.; Equations of The Second Kind is antiplatelet class, and such as COX-1 inhibitor and adp receptor antagonist etc., such medicine is mainly used in preventing and treating arterial thrombus; 3rd class is fibrinolytic agent, be mainly used in lysed blood formed fibrin.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, such as clopidogrel and aspirin etc. The shortcoming of these medicines is that bleeding risk is relatively larger. And as the PAR-1 antagonist of newfound antiplatelet class antithrombotic reagent, then there is less bleeding risk, therefore this compounds can as the very promising medicine for the treatment of arterial thrombus.
The invention discloses the class PAR-1 antagonist containing alkoxyphenyl radical and diene adamantane structure, they may be used for preparing the medicine of anti-arterial thrombus disease.
Summary of the invention
It is an object of the present invention to provide a kind of compound with formula I with good anti-thrombosis activity and pharmaceutically acceptable salt thereof.
It is a further object to provide preparation and there is the compound of formula I and the method for pharmaceutically acceptable salt thereof.
It is also another object of the present invention to provide the compound containing formula I and pharmaceutically acceptable salt as effective ingredient, and the Pharmaceutical composition of one or more pharmaceutically acceptable carriers, excipient or diluent, and the application in treatment arterial thrombus.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of formula I and has following structural formula:
Wherein, R is selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C8.
The preferably following compound with formula I,
More preferably the following compound with formula I,
The method of synthesis compound of Formula I:
Compound II per synthesizes (US4001223) according to literature method. Compound II per and PPh3Being obtained by reacting quaternary salt, then use highly basic to process and obtain Wittig reagent, then react with III, the diene obtained uses I2Alltrans diene IV is obtained after process; IV hydrolysis obtains V; V and VI is reaction under condensing agent exists, and obtains product I.
Wherein, described highly basic is selected from positive fourth lithium, isobutyl lithium, tertiary Ding Li, hexamethyl two silicon nitrilo sodium, hexamethyl two silicon nitrilo potassium, hexamethyl two silicon nitrilo lithium, lithium diisopropylamine; Described condensing agent is selected from N, N'-dicyclohexyl carbodiimide, N-ethyl-N'-dimethylamino carbodiimides, carbonyl dimidazoles.
Wherein, R's is defined as described above.
The pharmaceutically acceptable salt of compound of formula I of the present invention, include, but are not limited to the salt formed with various mineral acid example hydrochloric acids, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid etc., also include the salt formed with various organic acid such as acetic acid, succinic acid, maleic acid, malic acid and each seed amino acid etc.
Compound of Formula I of the present invention has the antagonism of PAR-1, can as effective ingredient for preparing the medicine of antithrombotic aspect. The activity of compound of Formula I of the present invention is verified by external model.
The compound of Formula I of the present invention is effective in comparatively wide dosage range. The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or is administered for several times. The actual dosage taking compound of Formula I of the present invention can be determined according to relevant situation by doctor. These situations include: the condition of patient, route of administration, age, body weight, individual reaction to medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated. It should be noted that following embodiment is only for illustrating, and it is not intended to limit the present invention. Those skilled in the art all should within the protection domain required by the application claim according to the various changes that the teachings of the present invention is made.
Embodiment 1
2.43g (10mmol) Compound II per and 2.62g (10mmol) PPh3It is dissolved in the 20mL THF dried, refluxes under nitrogen protection overnight. After reactant mixture is cooled to room temperature, obtain a white opacity solution. It is cooled to-78 DEG C under nitrogen protection, slowly drips the hexane solution of 6.25mL (10mmol, 1.6M) n-BuLi. After dropwising, continue stirring one hour, then drip compound 1.28g (10mmol) III and be dissolved in the 2mLTHF solution made. After dropwising, reactant mixture is slowly ramped to room temperature, then backflow 1 hour. Reactant mixture pours in frozen water, stirring, with the dichloromethane extraction of 50mL �� 3, merges extraction phase brine It, and anhydrous sodium sulfate dries.Sucking filtration removes desiccant, adds 0.50g iodine, stir overnight under room temperature in filtrate. Reactant mixture 100mL5% hypo solution washs, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product IV; White solid, ESI-MS, m/z=275 ([M+H]+)��
1.37g (5mmol) compound IV is dissolved in 15mL methanol, adds the NaOH solution of 1mL30%, then temperature rising reflux 10 minutes. After reactant mixture cooling, pour in 100mL frozen water, regulate pH=2 with concentrated hydrochloric acid. With the dichloromethane extraction of 50mL �� 3, merging extraction phase brine It, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product V; White solid, ESI-MS, m/z=245 ([M-H]-)��
0.74g (3mmol) compound V and 0.61g (3mmol) compound VI-1 is dissolved in the 5mL THF dried, and adds 0.62g (3mmol) DCC, stirs overnight under room temperature. TLC shows that reaction completes. After reactant mixture cooling, pouring in 100mL frozen water, with the dichloromethane extraction of 50mL �� 3, merge extraction phase brine It, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product I-1; White-yellowish solid, ESI-MS, m/z=429 ([M-H]-)��
Embodiment 2-5
With reference to the method for embodiment 1, synthesize the following compounds with formula I.
The preparation of embodiment 6 reference compound D1
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes the following formula: compound D1 (unexposed) found in experimentation, as drug effect reference compound.
Synthetic method is as follows:
2.43g (10mmol) Compound II per and 2.62g (10mmol) PPh3It is dissolved in the 20mL THF dried, refluxes under nitrogen protection overnight. After reactant mixture is cooled to room temperature, obtain a white opacity solution. It is cooled to-78 DEG C under nitrogen protection, slowly drips the hexane solution of 6.25mL (10mmol, 1.6M) n-BuLi. After dropwising, continue stirring one hour, then drip compound 1.28g (10mmol) III and be dissolved in the 2mLTHF solution made. After dropwising, reactant mixture is slowly ramped to room temperature, then backflow 1 hour. Reactant mixture pours in frozen water, stirring, with the dichloromethane extraction of 50mL �� 3, merges extraction phase brine It, and anhydrous sodium sulfate dries. Sucking filtration removes desiccant, adds 0.50g iodine, stir overnight under room temperature in filtrate. Reactant mixture 100mL5% hypo solution washs, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product IV; White solid, ESI-MS, m/z=275 ([M+H]+)��
1.37g (5mmol) compound IV is dissolved in 15mL methanol, adds the NaOH solution of 1mL30%, then temperature rising reflux 10 minutes. After reactant mixture cooling, pour in 100mL frozen water, regulate pH=2 with concentrated hydrochloric acid. With the dichloromethane extraction of 50mL �� 3, merging extraction phase brine It, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product V; White solid, ESI-MS, m/z=245 ([M-H]-)��
0.74g (3mmol) compound V and 0.52g (3mmol) compound VI-5 is dissolved in the 5mL THF dried, and adds 0.62g (3mmol) DCC, stirs overnight under room temperature.TLC shows that reaction completes. After reactant mixture cooling, pouring in 100mL frozen water, with the dichloromethane extraction of 50mL �� 3, merge extraction phase brine It, anhydrous sodium sulfate dries. Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains the sterling of product D1; White solid, ESI-MS, m/z=399 ([M-H]-)��
Embodiment 7 extracorporeal platelet aggregation inhibition test
In 96 orifice plates, concentrate the pharmacology test carrying out material at TRAP (Glycoprotein) platelet aggregation induced. Syringe is previously added the sodium citrate solution of 3.13%, then the blood of suction 20mL healthy volunteer, it is centrifuged 20 minutes under 1500g, will be enriched in hematoblastic blood plasma (PRP) and separate and process with the amount of 1 �� LPGE1 solution (alcoholic solution of 500 �� g/mL)/mLPRP. After at room temperature hatching 5 minutes, it is centrifuged under 1200g 20 minutes to remove leukocyte. PRP without leukocyte is transferred to 5mL/ part in the PP pipe of 15mL in batches, and centrifugal under 3600g make pellet platelets. Then, drain upper plasma, the pellet platelets deriving from 5mLPRP is suspended in 1mLTyrode (120mMNaCl, 2.6mMKCl, 12mMNaHCO again3, 0.39mMNaH2PO4, 10mMHEPES, 0.35%BSA, 5.5mM glucose, pH=7.4) in, and regulate the platelet count to 3 �� 105/ �� L with Tyrode. By this for the 13mL cell suspension 10mMCaCl with 866 �� L2Solution-treated, is drawn in 96 orifice plates with the amount of every hole 120 �� L, has added 15 �� L materials to be tested in the hole of 96 orifice plates in advance. At room temperature dark is hatched 30 minutes, add 15 �� LTRAP solution (70-100 ��M) as agonist, SpectraMax vibrates 20 minutes at 37 DEG C, kinetics is noted down under 650nm, calculate the area under curve of negative control (tyrode/DMSO) and positive control (15 �� L agonist/DMSO), and difference is decided to be 100%. Compound to be tested is aspirated with the form of serial dilution thing, is measured in duplicate, the same AUC measuring each material concentration, calculate AUC compared with the control and suppress %. IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %50Value. Following table gives result.
| Compound | The suppression IC of platelet aggregation50(��M) |
| I-1 | 0.52 |
| I-2 | 1.06 |
| I-3 | 0.73 |
| I-5 | 1.61 |
| Reference compound D1 | 0.94 |
As can be seen from the above table, the compound of the present invention all shows good inhibiting effect in platelet aggregation test.
Claims (5)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R is selected from H, C1-C5Alkyl, C3-C8Cycloalkyl.
2. claim 1 is defined compound of Formula I and pharmaceutically acceptable salt, be selected from:
3. claim 2 is defined compound of Formula I and pharmaceutically acceptable salt, be selected from:
4. synthesize the compound of the arbitrary defined formula I of claim 1-3 and the method for pharmaceutically acceptable salt thereof:
Compound II per and PPh3Being obtained by reacting quaternary salt, then use highly basic to process and obtain Wittig reagent, then react with III, the diene obtained uses I2Alltrans diene IV is obtained after process; IV hydrolysis obtains V; V and VI is reaction under condensing agent exists, and obtains product I; Wherein said highly basic is selected from positive fourth lithium; Described condensing agent is selected from N, N'-dicyclohexyl carbodiimide, N-ethyl-N'-dimethylamino carbodiimides, carbonyl dimidazoles;Described in the definition of R such as claim 1-3 is arbitrary.
5. the application in preparation treatment thrombotic medicine of any one of claim 1-3 is defined compound of Formula I and pharmaceutically acceptable salt.
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| WO1997048696A1 (en) * | 1996-06-20 | 1997-12-24 | Klinge Pharma Gmbh | Pyridyl alkene- and pyridyl alkine- acid amides as cytostatics and immunosuppressives |
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